Vesicle transporter GOLT1B mediates the cell membrane localization of DVL2 and PD-L2 and promotes colorectal cancer metastasis

Abstract

Background Colorectal cancer (CRC) is the third most diagnosed and second leading cause of cancer death worldwide. Hallmark proteins processing is usually dysregulated in cancers. Finding key regulatory molecules is of great importance for CRC metastasis intervention. GOLT1B is a vesicle transport protein which is involved in cytosolic proteins trafficking. However, its role in cancer has never been addressed. Methods CRC cell lines and subcutaneous xenograft animal model were utilized to investigate the biological function of GOLT1B. Patients samples were used to validate the correlation between GOLT1B and clinical outcome. In vivo targeted delivery of GOLT1B-siRNA was investigated in PDX (Patient derived tumor xenograft) model. Results We found that GOLT1B was highly expressed in CRC, and was an independent prognostic marker of overall survival (OS) and progression free survival (PFS). GOLT1B could promote CRC metastasis in vitro and in vivo. GOLT1B overexpression could increase DVL2 level and enhance its plasma membrane translocation, which subsequently activated downstream Wnt/β-catenin pathway and increase the nuclear β-catenin level, hence induce epithelial-mesenchymal transition (EMT). In addition, GOLT1B could also interact with PD-L2 and increase its membrane level. Co-culture of GOLT1B-overexpresed CRC cells with Jurkat cells significantly induced T cells apoptosis, which might further promote cancer cell the migration and invasion. Further, targeted delivery of GOLT1B siRNA could significantly inhibit tumor progression in GOLT1B highly expressed PDX model. Conclusion Taken together, our findings suggest that the vesicle transporter GOLT1B could promote CRC metastasis not only by assisting DVL2 translocation and activating Wnt/β-catenin pathway, but also facilitating PD-L2 membrane localization to induce immune suppression. Targeted inhibition of GOLT1B could be a potential therapeutic strategy for CRC treatment.

Multi-Omics Analyses Revealed GOLT1B as a Potential Prognostic Gene in Breast Cancer Probably Regulating the Immune Microenvironment

“…Besides, high expression of GOLT1B suggests poor prognosis of colorectal cancer, and induces immunosuppression by promoting PD-L2 membrane localization (7). Consistent with the previous report, our study revealed that the expression of GOLT1B was higher in breast cancer tissues than normal tissues (Figure 1).…”

“…One current study has uncovered that the overexpression of GOLT1B can elevate the cell membrane level of DVL2, then activate Wnt/bcatenin pathway, increase the content of nuclear b-catenin, and subsequently induce the process named epithelial-mesenchymal transformation. On the other hand, GOLT1B also promotes the migration and invasion of colorectal cancer via inducing T lymphocyte apoptosis (7). Poorer prognosis has been observed in patients with GOLT1B amplifications in lung adenocarcinoma (8).…”

Wnt signaling in colorectal cancer: pathogenic role and therapeutic target

“…GOLT1B is a vesicle transport protein involved in cytoplasmic protein transport. Overexpression of GOLT1B can increase the level of DVL2 and enhance its plasma membrane translocation, then activate the downstream Wnt/β-catenin pathway and increase the level of nuclear β-catenin, thereby inducing epithelial-mesenchymal transition (EMT) [ 112 ]. DCZ0415, a small molecule inhibitor against TRIP13, inhibits EMT and metastasis in colorectal cancer by inactivating the FGFR4/STAT3 axis and the Wnt/β-catenin pathway [ 113 ].…”

Evolving landscape of PD-L2: bring new light to checkpoint immunotherapy

“…Others GOLT1B. Golgi transport 1 B (GOLT1B) as a vesicle transporter that participates in protein trafficking in cytoplasm increases PD-L2 expression and facilitates PD-L2 membrane localization in colorectal cancer to promote apoptosis of T cells and decreases IFN-γ expression, which in turn promotes migration and invasion in CRC [30]. MMP9/13.…”